4-pregneno-[3, 2-c] pyrazoles and processes of preparing them



United States 3,067,193 4-PREGNENO-[3,2-c]PYRAZOLES AND PROCESSES OF PREPARING [HEM Max Tishler, Westfield, N.J., Nathan G. Steinberg, Brooklyn, N.Y., and Ralph F. Hirschmann, Scotch Plains, N.J., assignors to Merck & Co., Inc., Railway, N.J., a

corporation of New Jersey No Drawing. Filed Dec. 1, 1961, Ser. No. 156,465 21 Claims. (Cl. 260-239.5)

wherein R is fi-halogen, B-hydroxy or keto, but fi-halogen is present at R only when X is halogen, R is a-fluoro, hydrogen or a-methyl, R is hydrogen, oc-methyl, methyl, or methylene, R is hydrogen, hydroxy, acyloxy or fluoro, R is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or acyl and X is hydrogen or halogen, but hydrogen is present at not more than three of the four positions R R R and X, and wherein any acyl group present as an acyloxy group at R; may be the same or difierent from any acyl group present at R N-substituted-pyrazole compounds having structure A are herein designated at the 1'-substituted-4-pregneno-[3,2-c]pyrazoles, and N-substituted-pyrazo1e compounds having structure B are designated as the 2-substituted-4-pregneno- [3,2-c1pyrazo1es.

The above defined 4-pregneno-[3,2-c]pyrazo1es produced in accordance with the present invention possess high anti-inflammatory activity, and are especially effective for the treatment of arthritis and related diseases since they can be administered for their cortisone-like action in low dosage thereby minimizing undesirable side efieets.

* atent In preparing our novel chemical compounds, the start- 3,20-dione which may be identified by the following structural formula:

CHaOH I'll wherein R is fl-hydroxy or B-halogen, but fl-halogen is present at R, only when X is halogen, R is hydrogen, a-fluoro or a-methyl, R is hydrogen, a-methyl, ,8-methy1 or methylene, and X is hydrogen or halogen, but hydrogen is present at not more than two of the three positions R R and X. However, it is clear to those skilled in the art that other starting materials may be similarly converted to the desired end products.

Among the compounds which may be used as a starting material in the process of our invention are:

11B,17a,2l-tfihYdlOXY-16ce-Hl8thYl 4-pregnene-3 ,20-dione,

1 1p ,17u,2l-trihydroxy-16B-methyl-4-pregnene-3,ZO-dione,

1 1B, 17a,2l-trihydroxy-16 methyIene-4-pregnene-3 ,20-

dione,

1 15,17a,21-trihydroXy-6a-methyl-4 pregnene-3,ZO-dione,

1 1p,17oc,21-trihydroXy-6oc,16a-dimethyl-4-pregnene-3 ,20-

dione,

1 13,17 a,21-trihydroXy-6a, 1 6; 3-dimethyl-4-pregnene-3,20-

dione,

1 1,8, 21-trihydroXy-6a-rnethyl-16-methylene-4-pregnene-3 ,ZO-dione,

6a-fl1ioro-1 118,17a,21-trihydroxy-l6a-methyl-4-pregnene- 3 ,ZO-dione,

6a-fiuoro-1 1B,17a,21-trihydro;ry-16/3-methyl-4-pregnene- 3 ,20-dione,

6a-fiuoro-1 1,8,17a,21-trihydroXy-16-methylene-4-pregnene -3 ,2( )-dione,

9a-fiuoro-1 lfi,17a,21-trihydroxy-4-pregnene-3,20-dione,

9a-fluoro-1 1B,17a,21-trihydroxy-16a-methyl-4-pregnene- 3,20-dione,

9a-fillOrO-1 1p, 1701,21-trihydroxy-16fl-methy1-4-pregnene- 3 ,20-dione,

9a-fluoro-1 1p,17a,2l-trihydroxye16-methylene-4-pregnene-3 ,20-dione 9u-chloro-1 1 ,B,17oc,2 1-trihydroxyr4-pregnene-3,20-dione,

9a-chloro-1 1p,17,2i-trihydroxy-16a-methyl-4-pregnene- 3 ,20-dione, v

9oc-Ch1OI'O-1 1 p, 1711,21 -trihydroxy- 16,8-methyl-4-pregnene- 3 ,20-dione,

9a-chloro-115,17a,2l-trihydroxyr16-methylene-4-pregnene-3 ,ZO-dione,

9a-fiuoro-1 15,17a,21-trihydroxy-6u-methyl-4-pregnene- 3,20-dione,

9m-fluoro-11,8,17a,21-trihydroxy-6a,16a-dimethyl-4-pregnene-3 ,20-dione',

9u-fluoro-1 1,6,170:,21-trihydroXy-6a,16fl-dimethyl-4-pregnene-3 ,20-dione,

9a-chloro-1 1B, 170:,21-trihydroXy-6or-methyl-4-pregnene 3 ,2O-dione,

9a-ch1oro-1 1;6,17a,21-trihydroxy,-6a,16a-dimethyl-4-pregnene-3 ,20-dione,

9oc-Ch10rO-1 1/3,17a,21-trihydroxy-6 ,l6 3-dimethyl-4-pregnene-3,20-dione,

9a-chloro-1 l5,17a,21-trihydroxy-6a-rnethyl-16-methylene-4-pregnene-3 ,20-dione,

9a-chloro-1 1p,1711,21-trihydroxy-6u-fluor0-4-pregnene- 3,2--dione,

6a,9a-difluoro-1 1 8,17u,21-trihydroxy-16a-methyl-4- pregnene-3 ,ZO-dione, 1

6a,9a-difluoro-1 1,8,17a,2l-trihydroxy-16B-methyl-4-pregnene-3,20-dione,

60,9a-difitl0lO-l 1 3, 17a,21-trihydroxy-l 6-methylene-4- pregnene-3,20-dione,

9a-chloro-6a-fluoro-l 1B,17a,21-trihydroxy-4-pregnene- 3 ,ZO-dione,

9a-chloro-6a-fiuoro-1 15, l7a,21-trihydroxy-16a-methyl-4- pregnene-3 ,ZO-dione,

9a-chl oro-6a-fluoro-1 1 18, 1 711,2 1-trihydroxy-l6B-methyl-4- pregnene-3 ,ZO-dione,

9a-chloro-6 u-fluoro-l 1 it, 17a,21-trihydr0xy-'l 6-methylene- 4-pregnene 3,20-dione,

and the ll-keto-analogues of the above compounds;

9oz,l lfi-dich1oro-17a,2 l-dihydroxy-4-pregnene-3,20-dione,

9a,1 1fl-dichlorod7a,21-dihydroxy-16a-n1ethyl-4-pregene- 3,20-dione,

9a,1 lfi-dichloro-170:,2l-dihydroxy-16-methylene-4-pregnene-3 ,20-dione,

9a,l lB-dichloro-6a-fluoro-17a,21-dihydroxy-4-pregnene- 3,20-dione,

9oc,1 lB-dichloro-6a-fluoro-17u,21-dihydroxy-16a-methyl-4- pregnene-3,20-dione,

4-pregnene-3 ,20-dione,

90:, 1 1fi-dichloro-6a-fluoro-17a,21-dihydroxy-16-methylene- 4-pregnene-3 ,20-dione,

90:,1 l 3-dichloro-l7a,21-dihydroxy-6u-methyl-4-pregnene- 3 ,20-dione,

90:,1 l 3-dichloro-17a,21-dihydroxy-6u,'l6a-dimethyl-4- pregnene-3,20-dione,

9oz,1 1;8-dichloro-17a,21-dihydroxy-6a,16fl-dimethyl-4- pregnene 3 ,ZO-dione,

90:,11 8 dichloro-17a,21-dihydroxy-6u-methyl-16-methylene-4-pregnene-3 ,20-dione,

9a-bromo-l lfi-chloro-17a,2l-dihydroXy-4-pregnene-3,20-

dione,

9a-brorno-l lfi-chloro-17a,21-dihydroXy-l6a-methyl-4- pregnene-3,20-dione,

9a-bromo-1 1fi-chloro-17a,21-dihydroxy-16fi-methyl-4- pregnene-3,20-dione,

9a-brorno-1 1fi-chloro-17a,2l-dihydroxy-16-methylene-4- pregene-3 ,20-dione,

9abromo-l 1/3-chloro-1 7a,2 1-dihydroxy-6a-fluoro-4-pregnene-3 ,20-dione,

9abromo-11fi-chloro-17u,2l-dihydroxy-6a-fluoro-16ocmethyl-4-pregnene-3,ZO-dione,

9a-bromo-l1;8-chlorol7a,21-dihydroxy-6a-fluoro-1613- methyl-4-pregnene-3 ,20-dione,

9OL-bIOII10-1 lB-chloro-17,21-dihydroxy-6a-fiuoro-'16- methylene-4-pregnene-3 ,20-dione,

9a-bromo-1 lp-chloro-17:1,21-dihydroxy-6a-methy1-4- pregnene-3,20-dione,

9a-bromo-1 1 3-chloro-17a,2l-dihydroxy-6a,16u-dirnethyl- 4-pregnene-3,20-dione,

9u-bromo-l lB-chloro-17 x,21-dihydroxy-6a,l6fi-dimethyl- 4-pregnene-3 ,20-dione,

9u-bromo-l lfl-chlorol7a,2 I-dihydrOXy-Ga-methyI-l 6- methylene-4-pregnene-3,ZO-dione and the like.

The above named starting materials for our invention can be prepared by the introduction of the various substituents, namely the 16u-methy1-, 16fi-methyl-, l6-methylene-, 6a-methyl-,- 6oc-flll0lO-, 9a-fiuoro or the 9a-chloro groups into a 17a,21dihydroxy-4-pregnene-3,ZO-dione ac-- cording to known procedures capable of general applica-- tion. More than one substituent may be introduced into the unsubstituted steroid in any order, although it is genformula:

I CH2.

wherein R is B-hydroxy or fi-halogen but fi-halogen is present at R only when X is halogen, R R and X have the significance above defined, but hydrogen is present at not more than two of the three positions R R and X. For example, cold, concentrated HCl and formalin are added to a stirred suspension of the steroid in chloroform, cooled to about 0 C. The mixture is then allowed to come to room temperature and stirred for several hours to afford the corresponding 17a,20,20,2l-bis(methylenedioxy deriv ative.

In a preferred embodiment of our invention, the l7u,20,20,21-bis(methylenedioxy) 4 pregnene 3,11- dione compound which has the following formula:

wherein R R and X have the significance above defined, but hydrogen is present at not more than two of the three positions R R and X, is prepared by oxidation of the corresponding 11/3 hydroxy 17ot,20,20,21- bis(methylenedioxy)-4-pregnene-3-one, for example, with chromium trioxide in a non-aqueous base such as pyridine. If desired, however, the l7a,20,20,2l-bis(methylenedioxy)-4-pregnene-3,1l-dione may be prepared directly by the reaction of the 17a,2l-dihydroxy-4-pregnene- 3,11,20-trione with formaldehyde solution in the presence of an acid as described in the preceding step.

Upon treatment of an 11B-hydroxy-, l1B-halogen-, or 11 keto 17a,20,20,21 bis(rnethylenedioxy) 4 pregnene-3-one compound with an alkyl formate and sodium hydride in an inert atmosphere there is formed the corresponding l7oz,20,20,21-bis(methylenedioxy)-2-hydroxywherein R is 8-halogen, fi-hydroxy and/ or B-formyloxy-, or keto-, but ,B-halogen is present at R only when X is halogen, and R R and X have the significance above defined, but hydrogen is present at not more than two of the three positions R R and X. In a preferred embodiment of our invention, the steroid is dissolved in a solvent such as benzene and the resulting solution is cooled to room temperature and treated with ethyl formate. The air in the system is replaced with nitrogen, sodium hydride is added and the mixture is stirred at room temperature for several hours. i

The 170c,20,20,21 bis(methylenedioxy) 2 hydroxymethylene-4-pregnene-3-one compound reacts with hydrazine in an inert atmosphere to form the corresponding 170:,20,20,21 bis(methylenedioxy) 4 pregnene [3, 2-c]pyrazole.

Upon treatment of a l7u,20,20,2l-bis(methylenedioxy) 2 hydroxymethylene 4 pregnene 3 one compound with a lower alkanol in the presence of an acidic reagent such as a p-toluenesulfonic acid the corresponding 17a,20,20,21 bis (methylenedioxy) 2 alkoxymethylene-4-pregnene-3-one is formed. When the latter compound is reacted with a mono-substituted hydrazine, the corresponding N-substituted-4-pregneno-[3,2-c1pyrazole compounds are formed. The N-substituted-4-pregneno- [3,2-c]pyrazoles having structure A are designated as the 1 substituted 4 pregneno [3,2-c] pyrazoles, and the N-substituted-pyrazole compounds having structure B are designated as the 2-substituted-4-pregneno-[3, 2-c]-pyrazoles.

wherein R R R and X have the significance above defined, but hydrogen is present at not more than three of the four positions R R R and X, and wherein R is an alkyl, cycloalkyl, aralkyl or an aryl group. The products formed may be separated by chromatography.

Upon treatment of a 17a,20,20,21-bis(methylenedioxy) 2 hydroxymethylene 4 pregnene 3 one compound directly with a monosubstituted arylhydrazine, without the intermediate formation of the 2-alkoxymethylene-derivative, one isomer is generally formed in preponderant amounts, whereas when reacting the 17,20, 20,21 bis(methylenedioxy) 2 alkoxymethylene 4- pregnene-3-one compound with a monosubstituted arylhydrazine, significant amounts of both isomers are obtained. When these reactions take place with monosubstituted alkylhydrazines, mixtures may be obtained when starting with the Z-hydroxymethylene-steroid as well as with the 2-alkoxymethylene-steroid. A mixture of isomers may also result from the reaction of a monosubstituted hydrazine with a 2-hydroxymethylene-compound which possibly contains variable amounts of the 2-alkoxymethylene-derivative due to the operating procedures employed, for example, due to recrystallization in the presence of a trace of alcohol a solution of the 2-hydroxymethylene-compound from which acid has not been completely removed.

Among the monosubstituted hydrazines which may be used for the process of our invention are: alkylhydrazines, such as methylhydrazine, ethylhydrazine, propylhydrazines, butylhydrazines, B-hydroxyethylhydrazine, cycloalkylhydrazines; arylhydrazines including phenylhydrazine and the substituted phenylhydrazines, such as 0-, m-, and p-halophenylhydrazines, o-, m-, and p-tolylhydrazines, o-, m-, and p-alkoxyphenylhydrazines, o-, m-, and p-nitrophenylhydrazines, l-hydrazinonaphthalene, 2-hydrazinopyridine, 3-hydrazinopyridine, 4-hydrazinopyridine, 4-hydrazinopyridine oxide, and Z-hydrazinopyrimidine; aralkylhydrazines, such as benzylhydrazine and phenylethylenehydrazine.

There are thus produced the corresponding N-substituted-4-pregneno-[3,2-c]pyrazoles including: N-alkyl such as N-methyl-, N-ethyl-, N-butyl-, N-propyl-, N-(B-hydroxyethyl)-; N-cycloalkyl-; N-arylwhich may be derived from any aromatic nucleus, including N-phenyland the N-substituted-phenyl derivatives such as o-, m-,

and p-halophenyl; o-, m-, and p-tolyl-; o-, m-, and p-al- N-aralkyL, such as N-benzyland N-pheny1etheny1-4- pregnene-[3,2-c1pyrazoles.

The N-alkyl-4-pregneno-[3,2-c1pyrazoles may also be prepared by direct alkylation of the N-unsubstituted-4- pregneno-[3,2-c]pyrazo1es.

A 17a,20,20,21 bis(rnethylenedioxy) 11B hydroxy- 4-pregneno-[3,2-c]pyrazole which has a 9a-halo-substituent is preferably prepared by the following alternate route. Using the procedures described above, the halo 11fi,17a,21 trihydroxy 4 pregnene 3,20 dione is converted into the corresponding 17a,20,20,21-b-is- (methylenedioxy) 9oz halo hydroxy 4 pregnene-3-one. The latter compound is then oxidized to the 17a,20,20,21 bis (methylenedioxy) 9a halo 4 pregnene-3,11-dione, which is reacted with ethyl formate and sodium hydride to form the 2-hydroxymethylene-derivative. The latter compound is reacted with hydrazine, or a monosubstituted hydrazine, to give the corresponding 17a,20,20,2l bis(methylenedioxy) 9a halo 11 oxo- 4-pregneno-[3,2-c]pyrazole compound, or the N-substituted derivative thereof. The latter compound is then reduced to the corresponding 17a,20,20,2l-bis(methylenedioxy) 90c -halo 11 8 hydroxy 4 pregnene [3,2-c1- pyrazole compound, for example, by adding a saturated solution of sodium borohydride to a solution of the steroid in a mixture of triethylamine and isopropyl alcohol to which we prefer to add a little water, and allowing the mixture to stand overnight.

The N-unsubstituted 17a,20,20,21 bis(methylenedioxy)-4-pregneno-[3,2-c1pyrazole compounds are converted into N-acyl-derivatives having the following structures:

wherein R is ,B-halogen, fi-hydroxy or keto, but fl-halogen is present at R only when X is halogen; R R and X have the meaning described above, but hydrogen is present at not more than three of the four positions R R R and X; and wherein R is an acyl group, by treating with an acylating agent, eg. a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride or tertiary butyl acetyl chloride; a lower alkanoic anhydride or lower alkanoyl halide such as acetic anhydride, propionic anhydride or acetyl chloride; or a polybasic anhydride such as B,,B-dimethylglutaric anhydride, succinic anhydride and the like, in the presence of an organic base such as pyridine.

Upon treatment of any of the above described 170;,20, 2,21-bis(methylenedioxy) 4 pregneno [3,2-c1pyrazole compounds with a dilute organic acid, for example, a 60% aqueous solution of formic acid, the 17oc,20,20,21-bis (methylenedioxy)-protecting group is removed and there is obtained the corresponding 17a,2l-dihydroXy-20-oxo-4- pregneno-[3,2-c]pyrazoles which are represented by structures A and B;

CHzO R wherein R is B-halogen, ;8-hydroxy or keto, but fi-halogen is present at R only when Z is halogen; R R and X have the meaning described above; but hydrogen is present at not more than two of the three positions R R and X, and wherein R is acyl, alkyl, cycloalkyl, aryl or aralkyl and R is hydrogen, an acyl group corresponding to the organic acid used in this reaction, or a mixture of the two.

Any acyl groups present at R; and/ or at R may be removed by treating the steroid with sodium methoxide in methanol at room temperature to form the corresponding 17u,21-dihydroxy-20-oxo 4 pregneno-[3,2-c]pyrazole. Acyl groups present at the R position may be selectively removed by treatment with aqueous acetic acid.

The compounds of our invention include, among others, the following:

1 1B,17a,21-trihydroxy-20-oxo-4pregneno- [3 ,2-c] pyrazole,

1 118, :,21-trihydroxy-16a-methyl-2O-oXo-4-pregneno- [3,2-c1pyrazole,

1 1 3, l7a,21-trihydroxy-l6 3-methyl-2O-oxo-4-pregneno- [3,2-c1pyrazole,

1 1/3, 17oc,2 l-trihydroxy-16-methylene-20-oxo-4-pregneno- [3 ,2-c] pyrazole,

1 1,6,17a,21-trihydroXy-6a-methyl-20-oxo-4-pregneno- [3 ,2-c] pyrazole,

11fl,17a,21-trihydroxy-6u,16a-dimethyl-20-oxo-4-pregneno- [3 ,2-c] pyrazole,

1 1B,17a,2l-trihydroxy-6a-methyl-16-methylene-20-oxo-4- pregneno- [3 ,2-c] pyrazole,

6a-fluoro-1 15, 1 711,2 1-trihydroXy-20-oxo-4-pregneno- [3,2-c1pyrazole,

6a-fluoro-1 1B,17a,21-trihydroxy-16a-methyl-20-oxo-4- pregneno- [3,2-c1pyrazole,

6a-fiuoro-1 15,17a,21-trihydroxy-16 3-methyl-20-oxo-4- pregneno- [3 ,2-c] pyrazole,

6a-fluoro-1 1/3, l7a,21-trihydroxy-16-methylene-20-oXo-4- pregneno- 3 ,2-c] pyrazole,

9a-chloro-1 1/3,17a,2l-trihydroxy-20-oXo-4-pregneno- [3 ,2-c] pyrazole,

9oc-ChlOI'O-1 lfi, 17a,21-trihydroxy-16a-methyl-20-oXo-4- pregneno- 3,2-c] pyrazole,

9a-chloro-1 1/8,17a,21-trihydroxy-16fi-rnethyl-20-oXo-4- pregneno- 3 ,2-c] pyrazole,

9oc-Ch1OIO-1 1B, 17a,21-trihydroxy-16-methylene-20-oxo-4- pregneno- [3,2-c1pyrazole,

9a-fiuoro-1 1,8, l7a,21-trihydroxy-6u-anethyl-20-0Xo-4- pregneno- 3,2-c] pyrazole,

9a-fluoro-1 1/3,l7a,21-trihydroxy-6a,16a-dirnethyl-20-oxo- 4-pregneno- [3,2-c1pyrazole,

1 Q 9oe-bromo-1 lfi-chloro-17a,21-dihydroxy-6oc,16,8-climethy1- 20-oxo-4-pregneno- [3 ,2-c] pyrazole and 9a-bromo-1-1,8-ch1oro-17a,21-dihydroxy-6u-methy1-16- methylene-ZO-oxo-4-pregneno- 3 ,2-c] pyrazole as Well as the 1'- and 2-alkyl-, the 1'- and 2-cycloalkyl-, the 1- and 2'-aryl-, and the 1'- and 2'-aralkyl-derivatives of all of the above named compounds.

The N-acyl-derivatives of the above described 17a,21- dihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazoles are preferably obtained by treating the corresponding N-acy1-17a, 20,20,21-bis(methylenedioxy) 4 pregneno-[3,2-c]pyrazole compound with a dilute organic acid to remove the 17a,20,20,21-bis(rnethylenedioxy)-protecting group.

The 21-acy1 derivatives of the above described 17a,21- dihydroXy-20-oXo-4-pregneno-[3,2-c]pyrazoles in which R is H may be prepared by heating an N-acyl-17a,21-dihydroxy-ZO-oxo 4 pregneno-[3,2-c]pyrazole 21-acy1ate with aqueous acetic acid, whereupon the N-acyl group is selectively removed.

The N-acy1-21-acylate derivatives of the above described 1701,21 dihydroxy-2U-oxo-4-pregneno-[3,2-clPYrazoles in which both acyl groups are the same may be prepared (1) by reacting a 17a,21-dihydroXy-20-oXo-4- pregneno-[3,2-c]pyrazo1e with two equivalents of an acylating agent or (2) by reaction of an N-acyl-17a,21-dihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole with one equivalent of an acylating agent in which the acyl group of the acylating agent is the same as the acyl group already present at the N-position of the pyrazole.

The N-acyl-21-acylate derivatives of the above described 17a,2l-dihydroxy 20 oXo-4-pregneno-[3,2-c]pyrazoles in which the acyl groups are different are prepared by reaction of an N-acyl-17a,21-dihydroxy-20-oxo-4-pregneno-[3,2--c]pyrazole with an acylating agent in which the acyl group of the acylating agent is difierent from the acyl group already present at the N-position of the pyrazole.

Acylating agents which can be used for this purpose include a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride, tertiary butyl acetyl chloride; a loweralkanoic anhydride or lower alkanoyl halide such as acetic anhydride, propionic anhydride or acetyl chloride; or a polybasic anhydride such as B,/ -dimethyl-glutaric anhydride, succinic anhydride and the like, in the presence of an organic base such as pyridine.

The 17 04,21 dihydroxy-20-oxo-4-pregneno-[3,2-c]-pyrazole is reacted with methane sulfonyl chloride in a nonaqueous base to form the 21-mesylate. A steroid in which R is hydrogen is preferably converted to the N-acyl derivative before undergoing this reaction.

The 1701,2 dihydroxy-20-oXo-4-pregneno-[3,2-0] -pyrazole 21-mesy1ate is heated with an alkali iodide to form the 21-iodo-compound. In a preferred method for carrying out this reaction, sodium iodide is added to the steroid dissolved in acetone and the resulting mixture is heated at reflux temperature for approximately one hour.

The 17cc hydroXy-Zl-iodo-2O-oXo-4-pregneno-[3,2-c]- pyrazole is heated Wtih an alkali bisulfite in a solvent to form the corresponding 21-des0Xy-compound which has structures A and B:

s ems i3 neutralization of the dihydrogen phosphate ester with an alkali methoxide. Treatment with additional amounts of alkali methoxide will convert an N-acyl-steroid (R -acyl) into the free amine (R -H) dialkali metal salt from which the dihydrogen phosphate can be obtained by contacting with an ion exchange resin.

The A, B, C and pyrazole rings are not shown in the above equation, as the substituent groups on these rings do not affect the course of reaction and in general are unchanged during reaction. R has the meaning above defined and X is halogen.

The 2 l-fluoro-l7a-hydroxy-20=oxo-4-pregneno- 3,2-c] pyrazoles are prepared from the corresponding l7a,2.ldihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole 21 mesylate by heating with an alkali fluoride in a solvent to form amixture of a 17m,2i-epoxy-compound and the corresponding 21-fluoro compound. These compounds are separated by partition chromatography, or by chromatography on a Weak adsorbent such as silica gel. There is thus obtained the 21-fluoro-derivatives of all of the compounds named on pages 36.

The ZI-fiuoro-derivatives are represented by structures A and B:

wherein R R R R and X have the significance above described. All of the 4-pregneno-[3,2-c]pyrazoles described in the foregoing structures form salts such as the hydrochloride, sulfate, chlorate, perchlorate, picrate and trichloroacetate, on treatment with the corresponding acid. Formation of crystalline salts, especially the hydrochloride salts, provides a means of isolating the 4-pregneno-[3,2-c1pyrazoles.

A further embodiment of our invention comprises novel pharmaceutical compositions containing the novel 4-pregneno-[3,2-c1pyrazoles exemplified in the foregoing structures.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation. Details of the above described reactions are to be found in the examples.

14 Example 1 To a suspension of 25.0 g. of l1fi,l7a,21-trihydroxy- 16a-methyl-4-pregnene-3,2'0-dione in 1.5 l. of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydro chloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows tWo U.V. absorbing spots near the solvent front (methanol-formamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 g, aliquot is recrystallized three times from a mixture of benzene and n-hexane to give l7a,2(),2-O,2l-bis(methylenedioxy)-11B- hydroxy-16a-methyl-4-pregnene-3-one which is used in the subsequent step of the synthesis without further purification.

A solution of 400 mg. of l7a,20,20,2l-bis(methylenedioxy) -1 l fl-hydroxy-l 6a-methyl-4-pregnene-3-one in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into 'water, and the aqueousmixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous. sulfuric acid at about 0 C., and then with Water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17u,20,20,21-bis(methylenedioxy) -l6u-methyl 4-pregnene-3',l l-dione.

The 17a,20,20,2l-bis(methylenedioxy) 16a methyl- 4-pregnene-3,1'l-dione (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96. ml. of freshly distilled ethyl formate. The air in the systemis replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17u,2(),20,2l-bis(methylenedioxy) 2-hydroxymethylene- 16a-methyl-4-pregnene-3 ,l l-dione.

The 17a,20,20,Zl biS (methylenedioxy) -2-hydroxymethylene-l6a-methyl-4-pregnene-3,ll-dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evapo rated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at C. for 1 hour in high vacuum to give 17a,20,20,2l bis (methylenedioxy) 16amethyl-l'l-oxo-4-pregneno-[3,2-c]pyrazo1e.

To a solution of 100 mg. of l7a,20,20,21- bis(methy1- enedioxy) 16oz methyl-11-oxo-4-pregneno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and Water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acety1-17a,20,20,2lbis(methylenedioxy) 16a methyl 11-oxo-4-pregnen0- [3,2-c]pyrazole which is isolated by the addition of Water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N- acyl-derivative.

The N-acetyl 17a,20,20,21-bis(methylenedioxy)46amethyl-11-oxo-4-pregneno-[3,2-c]pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl-17a,21-dihydroxy 16oz methyl 11,20 dioxo- 4-pregneno-[3,2-c]pyrazole and N-acetyl 21-formyloxy- 17a-hydroxy-l6a-methyl 11,20-dioxo-4-pregneno-[3,2-c] pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with nhexane. The residue is Washed with water, filtered and dried to constant weight to give 17,21-dihydroxy-16amethyl-l1,20-dioxo-4-pregneno-[3,2-c]pyrazole.

To a solution of 100 mg. of N-acetyl-l7u,2l-dihydroxyl6a-methyl-l1,20-dioxo-4-pregneno-[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-17a,2l-dihydroxy-l6ot-methyl-11,20 dioxo 4-pregneno-[3,2-c]pyrazole 2l-acetate which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N- acetyl-17a,21-dihydroxy-16m methyl 11,20 dioxo 4- pregneno-[3,2-c1pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 17 a,2l-dihydroxy-16a-methyl-1 1,20-dioxo-4-pregneno-[3,2-c]pyrazole, and using two milliequivalents of another acylating agent there is obtained the corresponding N-acyl-21-acylate thereof.

A solution of 5.73 g. of N-acety1-17a,21-dihydroxy-16w methyl-11,20-dioxo-4-pregneno-[3,2-c1pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extracts are washed with water and with saturated sodium i6 bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 17a,21-dihydroxy-16ot-rnethyl 11,20 dioxo 4 pregneno-[3,2-c]pyrazole 2l-acetate.

To a solution of mg. of N-acetyl-17a,21-dihydroxy a methyl 11,20 dioxo 4 pregneno [3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for .a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-17a,2l-dihydroxy-l6u-methyl- 11,20-dioxo-4-pregneno- [3,2-c]pyrazole 21 -mesylate.

To a 180 mg. of N-acetyl-l7u,21-dihydroxy-l6amethyl 11,20 dioxo 4 pregneno [3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-l7u-hydroxy-21-iodo-l6w methyl-1 1,20-dioxo-4-pregneno- [3,2-c] pyrazole.

The N acetyl 17a hydroxy 21 iodo l6a-methyl-l1,20-dioxo-4-pregneno-[3,2-c1pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisullite and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyla hydroxy 16a methyl 11,20 dioxo 4 pregneno-[3,2-c]pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 17ot-hYd1'OXY-l6ozmethyl-l1,20-dioxo-4-pregneno-[3,2-c]pyrazole.

To a solution of 62 mg. of N-acetyl-17u,2l-dihydroxy- 160a methyl 11,20 dioxo 4 pregneno [3,2-c1pyrazole 2l-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl- 17oc,21 epoxy 16a methyl 11,20 dioxo 4 pregneno- 3 ,2-c] pyrazo'e and N-acetyl-Z1-fluoro-17a-hydroxy- 16oz methyl 11,20 dioxo 4 pregneno [3,2-c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 21-flllOI'O-17OL-hydroxy 16oz methyl 11,20 dioxo 4 pregneno- [3,2-clpyrazole.

In accordance with the above procedures, but starting with the 11,8,17a,2l-trihydroxy-16/3-methy1-4-pregnene- 3,20-dione in place of the 11;3,17a,21-trihydroxy-16amethyl-4-pregnene-3,20-dione, there are obtained as products the corresponding 17a,2l-dihydroxy-16fl-methyl- 11,20-dioxo-4-pregneno-[3,2-c]pyrazole, and the N-acyl-, the 21-acylate, and the N-acyl-Zl-acylate derivatives 17 thereof; 17oz hydroxy 16/3 methyl 11,20 dioxo- 4-pregneno-[3,2-c]pyrazole and the N-acyl-derivatives thereof; and the 2l-fluoro-l7or-hydroxy-l6flemethyhl1,20- dioxo-4-pregneno-[3,2-c1pyrazole and the N-acyl derivatives thereof.

In accordance with the above procedures, but starting with the 1 1 B, 17 01,2 l-trihydroxy-l6-methylene-4-pregnene- 3,20-dione in place of the 11B,17m,2l-trihydroxy-16amethyl-4-pregnene-3,ZO-dione, there are obtained as products the corresponding l7zx,2l-dihydroxy-16-methylenel1,20-dioxo-4-pregneno-[3,2-c]pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-Zl-acylate derivatives thereof; the 17a-hydroxy-16-methylene-11,20-dioxo-4- pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof; and the 2l-fluoro-17a-hydroxy-16-methylene-1l, 20-dioxo-4-pregneno-[3,2-c1pyrazole and the N-acyl derivatives thereof.

Example 2 To a suspension of 25.0 g. of 60z-fl1101O-l1/3,l7a-2ltrihydroxy-4-pregnene-3,20-dione in 1.5 liters of alcoholfree chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is backextracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two UV. absorbing spots near the solvent front (methanolforrnamide 2:1 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 6cc-fiUOIO-l7a,20,2(3,21- bis (methylenedioxy) 11,8-hydroxy-4-pregnene-3-one, which is used in the subsequent step of the synthesis without further purification.

The l7u,20,20,21-bis(methylenedioxy)-6a-fiuoro-11,8- hydroxy-4-pregnene-3-one (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred. magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21-bis(methylenedioxy)-6a-fiuoro-11 3-hydroxy-2 hydroxymethylene 4- pregnene-3-one.

The 17a,20,20,21 -bis (methylenedioxy) -6ocfi110r0-l 118- hydroxy-Z-hydroxymethylene-4 pregnene 3 one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour 18 in high vacuum to give 17a,20,20,21-bis(methylenedioxy)-6u-fluoro-1lfi-hydroxyl-pregneno [3,2-c] pyrazole.

To a solution of 100 mg. of l7ot,20,20,21-bis(methylenedioxy)-6ot-fluoro-l1fi hydroxy 4 pregneno [3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is S), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about C. in vacuo to afford the N-acetyl-l7a,20,20,2l-bis(methylenedioxy)-6a-fluoro-1lB-hydroxy-4-pregneno [3,2-c] pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The Nacetyl-17a,20,20,2l bis(methylenedioxy) 6afiuoro-11fi-hydroxy-4 pregneno [3,2 c]pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a.60% aqueous solution of formic acid for about 30 minutes. The'excess reagent is removed in vacuo using a water bath at about C. as the source of heat. The residue is flushed four times with n-hexane and then dried at C. in high vacuum to give a solid which is a mixture of N-acetyl-6u-fluoro-11p,17a,21-trihydroxy-2O oxo 4- pregneno-[3,2-c]pyrazole and N-acetyl-6a-fluoro-21-formyloxy-l1fl,17otdihydroxy-20 oxo 4 pregneno [3,2- c]pyrazole, which compounds are separated by chromatography. A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml, of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 6ot-fluoro-11fl,17a,21- trihydrxy-ZO-oxo-4-pregneno- 3,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-6rx-fiuoro-llp, l7a,21-trihydroxy-20-oxo-4-pregneno[3,2-c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and Water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-6a-fluoro-1113,170, 21-trihydroxy-20-oxo-4-pregneno- 3 ,2-c] pyrazole 21-acetate which is isolated by addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acetyl-6e-fluoro-l1/8,17a,21-trihydroxy-20 oxo 4- pregneno-[3,2-c]pyrazole 2l-acylate.

In accordance with the above procedure, but starting with the 6a-fiu0I'O-1l 3,l7u,21 trihy-droxy 20 oxo 4- pregneno-[3,2-c]pyrazole, and using two equivalents of another acylating agent there is obtained the correspond! ing N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-acetyl-6or-fluoro-l16,1711, 21-trihydroxy-20-oxo-4 pregneno [3,2-c]pyrazole 2lacetate in 60 ml. of (v./v.) acetic acid isrefluxed for 1.5 hours. This solution is diluted with 400 ml. of

ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords the 6u-fluoro-11,8,17e,2l-trihydroxy-20-oxo- 4-pregnen0- [3,2-c1pyrazole 21-acetate.

To a solution of 85 mg. of N-BCElIYl-6oc-flllGIO-11,3,1705, 21 trihydroxy 20 oxo 4 -pregneno [3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to C. is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-6e-fiuoro-11,8,17a,21- trihydroxy 20 oxo 4 pregnene [3,2-cjpyrazole 21- mesylate.

To 180 mg. of N-acetyl-6a-fluoro-11p,17e,21-trihydroxy 20 oxo 4 pregnene [3,2-c1pyrazole 21- mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-6a-fiuoro-l118,17a-dihydroxy-21-iodo-20- oxo-4-pregneno-[3,2-c]pyrazole.

The N acetyl 60c fluoro 1119,17 dihydroxy 21- iodo 20 oxo 4 pregneno [3,2-c1pyrazole is dissolved in a mixture of ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite and the mixture is heated under reflux for a period of about one hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-6ot-fiuoro-11e,17a-dihydroxy-20-oxo-4- pregneno-[3,2-clpyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with Water, filtered and dried to constant weight to give 6a-fluoro-11fi, 17adihydroxy 20 oxo 4 pregneno [3,2-c]pyrazole.

To a solution of 62 mg. of N-acetyl-6a-fiuoro-11,8,17ot, 21-trihydroxy 20 oxo 4 pregnene [3,2-clpyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformarnide is added enough anhydrous potassium fluoride to-assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-17a, 21-epoxy 60 fluoro 115 hydroxy 20 oxo 4- pregneno [3,2-c]pyrazole and N acetyl 611,21- difluoro 11 3.170; dihydroxy 20 oxo 4 -pregneno- [3,2-c]-pyrazole which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures, but starting with the corresponding N-acyl derivatives, there are obtained as products the N-acyl-ot-fiuoro-l1,8,17a-dihydroxy 20 oxo 4 -pregneno [3,2-c]pyrazole and the N acyl 60,21 difiuoro 116,17 dihydroxy 20- oxo-4-pregneno-[3,2-c]-pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and 20 flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give the 6a,2l-difluoro 11B,17a-dihydroxy 2O oxo 4 pregneno- [3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 1 1B,17 z,21-trihydroxy-6ct,16a-dimethyl-4-pregnone-3,20-dione in place of the 6oi-fiuoro-11fl,17a,21-trihydroxy-4-pregnene-3,20-dione there are obtained as products the corresponding 11B,1711.21-trihydroxy-6a,16u dimethyl 20 oxo 4 -pregneno [3,2-clpyrazole and the N-acyl-, the 2l-acylate, and the N-acyl-Zl-acylate derivatives thereof; the 115,l7u-dihydroxy-16a-dimethyl- 20 oxo 4 -pregneno [3,2-c1pyrazole and the N- acyl derivative thereof; and the 21-luoro-11,B,17a-dihydroxy 60c 16a dimethyl 20 oxo 4 pregneno- [3,2-c]pyrazole, and the N-acyl derivative thereof.

Example 3 To a suspension of 25.0 g. of 11/3,17u,21-trihydroxy- 6m methyl 4 pregnene 3,20 dione in 1.5 l. of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is backeXtracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated under reduced pressure. The residue is trituated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two U. V. absorbing spots near the solvent from (methanol-formamide 221 vs. benzene-n-hexane 1:1). A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and nhexane to give 17e,20,20,21-bis(methylenedioxy)-ll/i-hydroxy-6a-methyl-4-pregnene-3-one which is used in the subsequent step of the synthesis without further purification.

A solution of 400 mg. of 17a,20,20,21-bis-(methylenedioxy)-11fi-hydroxy-ot-methyl-4-pregneno-3-one in 4 ml. of pyridine is added to the complex formed by the addition of 400 mg. of chromium trioxide to 4 ml. of pyridine. The mixture is swirled until thoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueous mixture is extracted with ether and then twice with ethyl acetate. The combined ether and ethyl acetate extracts are washed with dilute aqueous sulfuric acid at about 0 C., and then water until neutral. The organic solvent layer is then dried, the solvents are evaporated therefrom in vacuo, and the residual crystalline material is purified by crystallization from a mixture of ethyl acetate and ether to give 17ot,20,20,21-his(methylenedioxy)-6amethyl-4-pregnene-3,1 l-dione.

The 17cc,20,20,21 bis(methylenedioxy) 6an1ethyl-4- pregnene-3,11-dione (1.350 g.) is dissolved in 23 mlof dry, but benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture isstirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product, is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crudeproduct which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again aciditied with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give l7a,20,20,2l bis(methylenedioxy)-2-hydroxymethylene-6a-methyl-4-pregnene-3,l l-dione.

The 17a,20,20,2l bis(methylenedi oxy) 2 hydroxymethylene-6a-methyl-4-pregnene-3,1l-dione (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a,20,20,21-bis(metl1ylenedioxy)-6amethyl l l-oxo-4-pregneno- [3,2-c1pyrazole.

To a solution of 100 mg. of 17a,2(i,20,2l-bis-(methylenedioxy) 6a-methyl-l1-oxo-4-pregneno-[3,2-c1pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8) and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about C. in vacuo to afford the N-acetyl-l7a,20,20,2lbis(methylenedioxy)-6u-methyl 11 oxo 4-pregneno- [3,2-c]pyrazole, which is isolated by the addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of the acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl l7a,20,20,2l-bis(methylenedioxy)-6amethyl-1l-oxo-4-pregneno-[3,2-c1pyrazole (720 mg.) is heated on a steam bath with 24 ml. of a 60% solution of formic acid for about 30 minutes. The excess reagent is removed in vacuo using a Water bath at about C. as the source of heat. The residue is flushed four times with n-hexane and then dried at C. in high vacuum to give an amorphous solid which is a mixture of N-acetyl- 17a,21-dihydroxy-6a-methyl 11,20 dioxo-4-pregneno- [3,2-c1pyrazole and N-acetyl-Z1-fonnyloxy-17othydroxy- 6a-methyl-l1,20-dioxo-4-pregneno-[3 ,2-c] pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxicle is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with Water, filtered and dried to constant weight to give l7et,2l-dihydroxy-6amethyl-1 1 ,20-dioxo-4-pregneno- [3 ,2-c] pyrazole.

To a solution of 100 mg. of N-acetyl-l7m,2ldihydroxy- 6a-methyl-11,20-dioxo-4-pregneno-[3,2-c1pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is l3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-acetyl-l7a,21-dihydroxy 60c methyl 11,20 dioxo-4-pregneno-[3,2-c] pyrazole 2l-acetate which is isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N acetyl 170.,21 dihydroxy 6w methyl 11,20? dioxo-4-pregneno- [3,2-c] pyr-azole 2 l -acylate.

In accordance with the above procedures, but starting with the 1704,21 dihydroxy 6a methyl 11,20 dioxo- 4-pregneno-[3,2-c1pyrazole, and using two millicquivatlents of another acylating agent, there is obtained the corresponding N acyl 17ot,21 dihydroxy 6a methyll1,20-dioxo-4-pregneno-[3,2-c]pyrazole 21-acylate.

A solution of 5.73 g. of the N-acetyl-17u.,2l-dihydroxy- 6a-methyl-11,20-dioxo-4-pregneno-[3,2 }pyrazole 21-acetate in 60 ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of icewater and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried and exaporated to dryness in vacuo. Recrystallization of the [resulting product affords the 17a,2l-dihydroxy-6a-methyl-l 1,20-dioxo-4-pregneno [3,2-c1pyrazole Zl-acetate. I

T o a solution of mg. of N-acetyl-l7a,2l-dihydroxy- 6rx-methyl-l1,20-dioxo-4-pregneno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-;,2l-dihydroxy-M-methyhl1,20- dioxo-4-pregneno-[3,2-c1pyrazole 2 l-mesylate.

To mg. of N-acetyl-17a,2I-dihydrOxy-Ga-methyll1,20-dioxo-4-pregneno-[3,2-cjpyrazole 2l-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, Washed with water, and dried to give N-acetyl 17a hydroxy 21 iodo 6a methyl 11,20 dioxo- 4-pregneno-[3,2-c1pyrazole.

The 'N-acetyl-l70L-l1Ydl'OXY-2l-iOd0-6ot-Il1d'thYl-l1,20-dloxo-4-pregneno-[3,2-c1pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-l7u-hydroxy-6amethyl-l 1,20-dioxo-4-pregneno- [3 ,2-c] pyrazole.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with nhexane. The residue is Washed with water, filtered and dried to constant weight to give 17OL-hydIOXy-60t-m6thYl- 1 1,20-dioxo-4-pregneno- [3 ,2-c] pyrazole.

To a solution of 62 mg. of N-acetyl-l7ot,21-dihydroxy- 6oz methyl 11,20 dioxo4-pregneno-[3,2-c]pyrazole 21- mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl-l7ot,21-epoxy-6amethyl-l1,20-dioxo-4-pregneno-[3,2-c]pyrazole and N- acetyl 21 fluoro 17a hydroxy 60c methyl 11,20- dioxo-4-pregneno-[3,2-c]pyrazole, which compounds are separated by partition chromatography, or by chroma- 75 tography on silica gel.

In accordance with the above procedures, but starting with the 9u-fluoro-1113,17ot,21-trihydroxy-4-pregnene-3,20- dione in place of the l1B,170:,2l-trihydroxy-4-pregnene- 3,20-dione there are obtained as products the corresponding 90: fiuoro-17a,21-dihydroxy-1l,20-dioxo-4-pregneno [3,2-c1pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-2l-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9a-fluorol7 x hydroxy 11,20 dioxo 4 pregneno [3,2-c1pyrazole and the N-acyl derivatives thereof; and the 906,21-dlfiuoro 17a hydroxy 11,20 dioxo 4 pregneno- [3,2-c1pyrazole and the N-acyl derivatives thereof.

In accordance with the above procedures, but starting with the 9a-fluoro-6wmethyl-1lfi,l7a,2l-trihydroxy-4- pregnene-3,20-dione in place of the 11B,17u,2l-trihydrox 6u-methyl-4-pregnene-3,ZO-dione, there are obtained as products the corresponding 9ot-fluoro-l7ot,2l-dihydroxy- 6ot-methyl-11,20-dioxo-4-pregneno-[3,2-c]pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two acyl groups may be the same or difierent; the 9a-fluoro-17ot-hydroxy-6d-methyl- 11,20-dioxo-4-pregneno-[3,2-c1pyrazole and the N-acyl derivatives thereof; and the 90,2l-difiuoro-lh-hydroxy- 60c methyl 11,20 dioxo 4 pregneno [3,2-c]pyrazole and the N-acyl derivatives thereof.

Example 4 To a suspension of 25.0 g. of llfl,l7ct,2l-trihydroxy- 16ot-methyl-4pregnene-3,ZO-dione in 1.5 liters of alcoholfree chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to aiford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography. A 2.425 g. aliquot is recrystallized three times from a mixture of benzene and n-hexane to give l7a,2 0,20,2l-bis (methylenedioxy) -l 1,8-hydroxy-l6amethyl-4--pregnene-3-one which is used in the subsequent step of the synthesis without further purification.

The l7oc,2D,20,21 bis(methylenediorty) l1,8-hydroxyl6u-rnethyl-4-pregnene-3-one (1.350 g.) is dissolved in 25 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 566 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magneticall at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with Water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts ar. again acidified with an excess of a saturated aqueous solu tion of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17e,20,2(l,21-bis(rnethylenedioxy)-ll5- hydroxymethylene-l 6ea-methyl-4-pregnene-3 -one.

The l7a,20,20,21-bis(methylenedioxy)-1lB-hydroxy-Z- hydroxymethylene-l6tx-methyl-4 pregnene 3 one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol treated with a solution of 6.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. he residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give l7u,ZO,ZQ,2l-bi3 (methylcnedioxy) 11B hydroxy 16a methyl 4- pregneno-[3,2-c1pyrazole.

To a solution of 100 mg. of 17a,20,20,2l-bis(methyl-' enedioxy) llfi -hydroxy 16a methyl 4 pregnene [3,2-c]pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and Water is then added. After standing for about minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with Water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is l-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then dis tilled at about C. in vacuo to afiord the N-acetyi 17a,20,20,2l-bis(methylenedioxy) 11p hydroxy 16amethyl-4-pregneno-[3,2-c1pyrazole which is isolated by the addition of Water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride there is obtained the corresponding N-acyl-steroid.

The N acetyl-17a,20,20,21-bis(methylenedioxy)-1l [1- hydroxy-l6ot-methyl 4-pregneno [3,2-c1pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 nn'nutes. The excess reagent is removed in vacuo using a water bath at about C. as the source of heat. The residue is flushed four times with n-hexane and then dried at C. in vacuum to give an amorphous solid which is a mixture of N acetyl l15,17a,21-trihydroxy-16a-methyl-20- oxo-4-pregneno-[3,2-c]-pyrazole and N-acetyl-Zl-formyloxy-l 118,l7a-dihydoxy16a-methyl-20-oxo-4 pregneno- [3,2-c1pyrazole which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give llfl,l7a,2l-trihydroxy- 16or-methyl-20-oxo-4-pregneno-[3,2-c]pyrazole.

To a solution of mg. of N-acetyl-llB,l7a,2l-trihydroxy 16cc methyl 2O 0x0 4 pregneno [3,2-c] pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and Water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The N-acetyll1fi,17a,2l-trihydroxy-l6ot-methyl-20-oxo 4 pregneno- [3,2-c1pyrazole 21-acetate is then isolated by addition of Water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N-acetyl 1l,8,l7a,2l trihydroxy 16e-methyl-20-oxo-4- pregneno-[3,2-c]pyrazole Zl-acylate.

In accordance with the above procedure, but starting with the l1 8,17e,21-trihydroxy-l6ot-methyl-2O-oxol-pregneno-[3,2-c]pyrazole and using two milliequivalents of 25 another acylating agent there is obtained the corresponding N acyl1lfi,17ot,21 trihydroxy-16ot-methyl-20-oxo-4- pregneno-[3,2-c]pyrazole 21 acylate.

A solution of 5.73 g. of N-acetyl-I1{3,l7rx,2l-trihydroxy- 16 a-methyl-20-oxo-4-pregneno- 3,2-c] pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-Water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 1l,6,17t,21 trihydroxy-l6ct-methyl-20-oxo-4-pregneno-[3,2-c]pyrazole 2l-acetate.

To a solution of 85 mg. of N-acetyl-l15,l7 x,21-trihydroxy 16u-methyI-Z0-oxo-4-pregneno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to C., is added to 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately one hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-l1B,l7ot,2l-trihydroxy-16a-methyl- 20-oxo-4-pregneno- [3,2-c] pyrazole 21-mesylate.

To 180 mg. of N-acetyl-l1fi,17a,21-trihydroxy-16amethyl 2O oxo-4-pregneno-[3,2-clpyrazole 21-mesylate dissolved in ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-l1/3,17a-dihydroxy-21-iodo-16a-methyl- -oxo 4-pregneno- [3,2-c1pyrazole.

The N acetyl-l 1B,17a-dihydroxy-2l-iodo-16 t-methyl- 20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. or" water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl- 116, l 7OL-dii1YdlOXY- 1 6a-methyl-2G-oxo-4-pregneno- 3 ,2-c] pyrazole.

To a solution of 52 mg. of N-a-cetyl-l1,8,17ot,2l-trihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl17a,21-epoxy-11fi-hydroxy-16amethyl-ZO-oxo-4-pregneno-[3,2-c]pyrazole and N-acetyl- 21 fluoro 11B,l7rx-dihydroxy-16a-methfl-ZO-OXO- l-pregneno-[3,2-c]pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the N-acetyl-Zl-fluoro-l1B,17adihydroxyl 6a-methyl-20-oxo-4-pregueno- [3,2-c1pyrazole is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The al-koxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and dried to constant weight to give the ZI-fluoro-l1/3,17a-dihydroxy-16ot-methyl-20- oxo-4 -pregneno- [3,2-c1pyrazoie.

in accordance with the above procedures, but starting with the 1lfi,l7oc,2l trihydroxy 60c methyll-pregnene 3,20-dione in place of the 11B,17oz,2l-trihydroxy-l6amethyll-pregnene-3,20-dione, there are obtained as products the corresponding 11B,17a,2l-trihydroxy-6ot-methyl- 26 20-oxo-4-pregneno-[3,2-c]pyrazole and the N-acyl-, the 21-acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two acyl groups may be the same or different; the 1113,17 a-dihydroxy-6u-methyl-20-oxo-4-pregneno- [3,2-clpyrazole and the N-a'cyl derivatives thereof; and the 21 fiuoro 115,17a dihydroxy-6wmethyl-20-oxo-4- pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof.

Example 5 To a suspension of 10 g. of 9a,1lB-dichloro-17a,21-dihydroxy-4-pregnene-3,ZO-dione in 475 ml. of alcohol-free chloroform and 300 ml. of methylene chloride, cooled to about 5 C. in an ice bath, is added with constant stirring 189 ml. of cold, concentrated hydrochloric acid and then 189 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 2 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed with water, then with a 5% solution of sodium bicarbonate and again with Water. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is flushed three times with methanol. Hot methanol is then added and the product is filtered and then crystallized from a mixture of methylene chloride and n-hexane to give l7ot,20,20,2l-:bis (rnethylenedioxy 9a, 1 1fl-dichloro-4-pregnene-3-one.

The 17a,20,20,2l-bis(methylenedioxy)-9m,lIB-dichloro-4-pregnene-3-one (500 mg.) is suspended in 8.5 cc. of dry benzene and treated with 0.15 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 225 mg. of sodium hydride (as a 58% dispersion in mineral oil is added). The system is again evacuated and titled with nitrogen. The mixture is stirred under nitrogen for /2 hour after which time 0.2 ml. of ethyl formate is added and the mixture is stirred magnetically at room temperature overnight. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as a sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,2lbis (methylenedioxy)-9u,l l B-dichloro-Z-hydroxy methylene-4-pregnene-3-one.

The 17a,20,20,21-bis(methylenedioxy)-9a,1 1,6 dichloro-2-hydroxymethylene-4-pregnene-3-one (65 mg.) is dissolved in 0.7 ml. of absolute ethanol and treated with a solution of 0.12 ml. of hydrazine hydrate dissolved in 0.12 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and petroleum ether is added to give a solid which is 17ot,20,20,2l-bis(methylenedioxy) -9a,1 1fl-dichloro-4-pregneno- [3 ,Z-c] pyrazole.

To a solution of mg. of l7ot,20,20,2l-bis(methylenedioxy) -9cc,1 10t-diCi11OI'O-4-pf6gHGIlO-[3,2-CJPYI'8ZO1fi in 2 ml. of pyridine is added one milliequivalent of propionic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30' minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to afford the N-propionyl- 27 17a,20,20,21-bis(methylenedioxy)-9a,115- dichloro 4 pregneno-[3,2-c1pyrazole which is isolated by the addition of water and filtration.

In accordance with the above procedures, but using an equivalent quantity of another acylating agent in place of propionic anhydride, there is obtained the corresponding N-acyl-derivative.

The N propionyl 17a,20,20,21-bis(methylenedioxy)- 9a.,1lfl-dichloroi-pregneno-[3,2,-c]pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-propionyl-9a,11fldichloro-l7a,2l-dihydroxy-20-oxo-4-pregneno [3,2 c] pyrazole and N-propiony1-9u,l1/3-dichloro-2l-formyloxy- 17a-hydroxy-20-oxo-4-pregneno-[3,2 c] pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with Water, filtered and dried to constant Weight to give 9a,11{3-dichlor0- l7a,21-dihydroxy-20-oxo-4-pregneno-[3,2-c1pyrazole.

To a solution of 100 mg. of N-propionyl-9m,11,B-dichloro-17a,21-dihydroxy-Z0-oxo-4-pregneno-[3,2-0] pyrazole in 2 ml. of pyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30' minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C., in vacuo. The product is then crystallized from a solvent; alternately, the product may be chromatographed on alumina to give the N-propionyl-9a,11fl-dichloro-17a,21- dibydroxy-20-oxo-4-pregneno- [3,2-c1pyrazole 2 l-acetate, which is isolated by crystallization of the appropriate eluate.

In accordance with the above procedure, but using an equivalent quantity of any other acylating agent in place of the acetic anhydride, there is obtained the corresponding N propionyl-9a,1lfl-dichloro-17a,21-dihydroxy-20- oxo-4-pregneno-[3,2-c1pyrazole 21-acylate.

In accordance with the above procedures, but starting with the 9oc,l1,8 dichloro 17a,21-dihydroxy-20-oxo-4- pregneno-[3,2-c]pyrazole and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-propionyl-9u,1IB-dichloro- 17u,2l-dihydroxy-20-oxo-4-pregneno-[3,2-c1pyrazole 21- acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product aiiords 9a,11,8-dichloro-17a,21-dihydroxy-20-oxo 4-pregneno-i3,2-c1pyrazole ZI-acetate.

To a solution of 85 mg. of N-propionyl-9ot,l15-di chloro-17a,21-dihydroxy-20-oxo 4-pregneno [3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate pregneno- [3,2-c] pyrazole which forms is recovered by filtration, washed with water, and dried to give N-propionyl-9u,11/3-dichloro-17a,21-dihydroxy-20-oxo-4-pregneno-[3,2-c1pyrazole 2l-mesylate.

To 180 mg. of N-propionyl-9a,l1/3-dichloro-17ot,21-dihydroxy-ZO-oxo-4-pregneno-[3,2-c1pyrazole 2l-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reiiux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-propionyl ,1LIB-dichloro-17a-hydroxy-21-iodo- 20-oxo-4-pregneno-[3,2-c]-pyrazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 nil. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-propionyl- 90:,116 dichloro-17u-hydroxy-21-iodo-20-oxo-4-pregneno- [3,2-c]-pyrazole.

The N-propionyl-9a,1 1fi-dichloro-l7a-hydroxy-21-iodo- 20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-propionyl- 9a,11,8-dichloro 17a-hydroxy-20-oxo-4-pregneno-[3,2-c] pyrazole.

To a solution of 62 mg. of N-propionyl-9a,115-dichloro 17a,2ldihydroxy-20-oxo-4-pregneno-[3,2-c1pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethylforma-mide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is then added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N- propionyl 9a,1 1,8 dichloro 1711,21 epoxy 20 oxo-4- and N-propionyl 90:,11B-dichloro-21-fluoro-17ot-hydroxy-20-oxo-4-pregneno [3,2-c] pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

A 500 mg. aliquot of the crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The akoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and dried to constant weight to give N-propionyl- 9a,11,6-dichloro 21 fiuoro-l7a-hydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole.

In accordance with the above procedures, but starting with the 9a-bromo-l1,6-chloro-17a,21-dihydroxy-4-pregnene-3,20-dione in place of the 9a,llB-diChlOr0-17oz,2ldihydroxy-4-pregnene-3,20-dione there are obtained as products the corresponding 9u-bromo-11B-chloro-17a,21- dihydroxy-20-oxo-4-pregneno-[3,2-c1pyrazole and the N acyl-, the 21 acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9a-bromo-1lfl-chloro-l7ot-hydroxy- 20-oxo-4-pregneno-[3,2-c]pyrazole and the N-acyl derivative thereof; and the 9a-bromo-11,6-chloro-21-fiuoro-l7uhydroxy-ZO-oxo-4-pregneno-[3,2-c1pyrazole and the N- acyl derivatives thereof.

The 904,1lfi-dichloro-17a,2l-dihydroxyl-pregnene 3,20- dione and the 9a-bromo-1lfi-chloro-17a,21-dihydroxy-4- pregnene-3,20-dione compounds, as weil as the substituted derivatives thereof (see columns 1, 2, and 3), used as start- 2% ing materials can be obtained in the following manner, starting from the corresponding 17ot,21-dihydroxy-4-pregnene-3,20-dione.

A solution of 400 mg. of 170:,2l-dihydroxy-4-pregnene- 3,20-dione in 2.0 ml. of dimethyl formamide, 0.8 ml. of pyridine and 0.4 ml. of methanesulfonyl chloride is allowed to stand at 75 C. for one hour. The mixture is cooled and water is added. The precipitate formed is filtered, washed with water, dried in air and purified by chromatography on alumina and elution with benzene. Crystallization gives 17a,2l-dihydroxy-4,9 1 l -pregnadiene-3,20-dione.

To a solution of 100 mg. of l7a,2l-dihydroxy-4,9(ll)- pregnadiene-3,20-dione in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and Water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo to aiford the l7a,2l-dihydroxy-4,9(l1)-pregnadiene-3,20- dione 2l-acetate which is isolated by the addition of water and filtration.

To a stirred, cooled (5 C.) solution of 17,21-dihydroxy-4,9(l1)-pregnadiene-3,20-dione-2l-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N-chlorosuccinim-ide (383 mg, 1.1 equivalent) followed immediately by an anhydrous solution of hydrogen chloride (104- mg.) in tetrahydrofuran (1.0 m1.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is poured into water (400 ml.). The resulting mixture is filtered and the residue is washed with water, and dried to yield a crude product. Crystallization from acetone gives 9a,l1fi-dichloro- 17o ,21-dihydroxy-4-pregnene-3,20-dione Zl-acetate.

A suspension of 904,11fi-dichloro-17a,21-dihydroxy-4- pregnene-3,20-dione Zl-acetate (1.0 g.) in 0.27 N methanolic perchloric acid (70 ml.) is stirred at room temperature for 17 hours. The reaction mixture is then poured into water (200 ml.) and filtered. The residue is washed with water and dried, giving a crude product, which is crystallized from acetone to yield 9a,ll[3-dichloro-l7o:,21-dihydroxy-4-pregnene-3,20-dione.

To a stirred, cooled O- C.) solution of l7ot,2l-dihydroxy-4,9(l1)-pregnadiene-3,20-dione 21-acetate (1.0 g.) and lithium chloride (4.0 g.) in glacial acetic acid (40 ml.) is added N-bromoacetamide (395 mg.) followed immediately by an anhydrous solution of hydrogen chloride (104 mg.) in tetrahydrofuran (1.0 ml.). Stirring is continued at room temperature for 3 hours, and the reaction mixture is precipitated with water and filtered. The residue is washed with water, and dried to yield a crude product. Crystallization from acetone gives 90.- bromo-ll B-cl1loro-l7a,2l-dihydroxy 4 pregnene 3,29- dione 21-acetate.

A suspension of 9u-hromo-l1dchloro-i7a,2-lrdihy- After standing for about 30 minutes, the product is exhours.

tracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and Water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 4 0 C. in vacuo to aiford the 911,11,B-diCl1lOIO-17oc,2l-dihydr0xY-4- pregnene3,20-dione 2l-acetate which is isolated by the addition of water and filtration.

Example 6 A 5 g. sample of 9CL-fiOl1l'O-1 1B,17et,2l-trihydroxy-16umethyl-4-pregnene-3,20-dione is dissolved in a mixture of 235 ml. of chloroform and 150 ml. of methylene chloride, cooled in an ice bath with stirring and treated with ml. of formaldehyde (37%). An equal volume (85 ml.) of cold concentrated hydrochloric acid is added from a funnel over a 5-minute interval with stirring and cooling. The mixture is stirred at room temperature for four The layers are separated and the organic layer is washed free of acid by washing three times with Water and then with a 5% solution of sodium bicarbonate. The organic layers are Washed free of bicarbonate, dried over magnesium sulfate and taken to dryness. The gummy residue is treated with enough hot methanol on a steam bath to effect trituration, and the resulting crystalline solid is separated by filtering the mixture while hot. (The filtrate is set aside and may deposit additional product overnight.) The crude product is dried to constant weight and purified by chromatography. The product is partially dissolved in 250 ml. of hot chloroform and diluted with an equal volume of hot benzene to complete solution. After cooling, the mixture is adsorbed in g. of basic alumina and eluted with benzene and chloroform to give 17a,20,20,21-blS(lTl6thyl]1dlOXy)-90t-fll1OIO-160tmethyl-1 lB-hydroxy-4-pregnene-3-one.

The 17u,20,20,2l-bis(methylenedioxy)-9a-fiuoro-l6otmethyl-11,B-hydroxy-4-pregnene-3-one (3.25 g.) is dissolved in 76 ml. of dry pyridine and added to a cold solution prepared by the cautious addition of 3.25 g. of chromium trioxide (in portions) to 34.7 ml. of cold pyridine. The mixture is allowed to stand at room temperature overnight. The mixture is poured into Water and extracted three times with ethyl acetate, avoiding excessive shaking especially during the third extraction. The combined ethyl acetate extracts are Washed three times with 1 N sulfuric acid and then with water until neutral. The combined ethyl acetate extracts are dried over magnesium sulfate and taken to dryness to give 2.94 g. of product. The product is dissolved in benzene, adsorbed on basic alumina and eluted with 8:2 benzene; chloroform to give 17a,20,20,21 bis(methylenedioxy)-9a-fiuoro-16 x-methyl- 4-pregnene-3,l l-dione.

A 2.60 g. sample of l7u,20,20,2l-bis(methylenedioxy)- 9e-fiuoro-l6e-rnethyl-4-pregnene-3,ll-dionc is dissolved in 95 ml. of dry benzene using dry equipment and treated with 2.43 ml. of freshly distilled ethyl formate. About 1.19 g. of a dispersion of sodium hydride in mineral oil (about 51%) is added, followed by about 1.19 g. of freshly prepared dry sodium methoxide (dried at about C. oil pump for 4 hours). The air in the system is again replaced with nitrogen and the mixture, which turns yellow at once, is stirred at room tem erature for one and one-half hours. At this point the color of the reaction mixture is a dark orange. The mixture is chilled in an ice bath and a cold, saturated solution of sodium dihydrogen phosphate is added gradually to decompose excess sodium hydride and neutralize the sodium methoxide. Ether is added and the layers are separated. The aqueous layers are back-extracted with ether and the combined organic layers are washed free of acid with Water and then extracted three to four times with a 5% aqueous solution of sodium bicarbonate. These extracts are set aside. The product is now extracted four to five times with a cold 2% aqueous soiution of sodium hydroxide. (In order to avoid emulsification, the aqueous alkali is gently poured into the separatory funnel and the layers are separated without shaking the funnel. The last two extracts may be shaken with care.) The dark liquor is back-extracted two times with ether, and finally acidified in the cold with saturated aqueous solution of sodium dihydrogen phosphate. The neutral ether-benzene fraction should be set aside and processed as described below. The product is extracted into ether, and the ether extracts are washed free of acid with a saturated solution of sodium chloride. After drying over magnesium sulfate, the ether solution is taken to dryness and the amorphous product is crystallized from methanol to give 17cc, 20,20,21 bis(methylenedioxy) 9a fluoro 2 hydroxymethylene-16a-methyl-4-pregnene-3,1l-dione. This material is satisfactory for use in the next step.

A 1.00 g. aliquot of 17a,20,20,21-bis(methyienedioxy)- 9o: fiuoro 2 hydroxymethylene 16cc methyl 4- pregnene-3,1l-dione is suspended in 44 ml. of absolute ethanol and treated with 0.38 ml. of hydrazine hydrate (99l00%). The air in the system is replaced with nitrogen and the mixture is quickly brought to the reflux temperature. After refluxing for one hour, the mixture is taken to dryness; the residual oil is treated with water and the resulting amorphous solid is removed by filtra- 'tion, Washed thoroughly with water and dried. The yield is about 900 mg. The crude product is dissolved in absozlute ethanol and concentrated in vacuo until the solid separates. The solid is redissolved by heating, and then allowed to crystallize slowly to afford 17a,20,20,21-bis- (methylenedioxy) 90 fluoro 16c: methyl 11 oxo- 4-pregneno-[3,2-c]pyrazole.

A 455 mg. aliquot of 17oc,20,20,21-bis(methylenedioxy) 900 fiuoro 16o: methyl ll oxo 4 pregneno-[3,2-c]pyrazole is suspended in 75 ml. of a solution of sodium borohydride in isopropanol which is prepared by suspending an excess of sodium borohydride in isopropanol, stirring vigorously for about minutes, and filtering to separate the excess of sodium borohydride. To the suspension is added an 0.816 ml. aliquot of a solution of 0.55 ml. of triethylamine in 1.45 ml. of isofpropanol. The mixture is stirred, and enough methylene chloride (about 30 ml.) is added, with cooling, to make the system homogeneous. One drop of water (ca 1/ 'ml.) is added and the mixture is stirred in a nitrogen atmosphere at room temperature overnight. Insolubles generally separate out in the course of the reaction. The mixture is then cooled, and the excess of sodium borohydride is decomposed by the addition of cold N hydrochloric acid. The mixture (pl-I ca 5) is taken to dryness in vacuo and the residue is washed with water and dried to give 17a,20,20,21-bis(methylenedioxy)-9uhuoro 115 hydroxy 16cc methyl 4 pregneno- 'To a solution of 100 mg. of l7u,20,20,2l-bis(methylenedioxy) 9a fluoro 11 8 hydroxy 16a methyl- 4-pregneno- [3,2-c1pyrazole in 2 ml. of pyridine is :added 0.5 ml. of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing :for about minutes, the product is extracted with ethyl acetate. he ethyl acetate extract is washed successively with water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate is then distilled at about C. in vacuo to afford the N acetyl 17a,20,20,21 bis(rnethylenedioxy) 9onfiuoro 115 hydroxy 16cc methyl 4 pregneno- [3,2-c]pyrazole which is isolated by the addition of water and filtration.

In accordance with the about: procedure, but using an equivalent quantity of another acylating agent in place 32 of acetic anhydride, there is obtained the corresponding N-acyl derivative.

The N acetyl 170:,20,Z0,21 bis(methylenedioxy)- c fiuoro 11B hydroxy a methyl 4 pregneno- [3,2-c1pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a Water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of N-acetyl-9a-fluoro-l1,8,17a,21-trihydroxy-16amethyl- 20-oxo-4-pregneno-[3,2-c1pyrazole and N-acetyl-9u-fiuoro 21 formyloxy 115,170 dihydroxy methyl- 20-oxo-4-pregneno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9a-fiuoro- 115,170 21 trihydroxy 16a-methyl-20-oxo-4-pregneno- [3,2-c]pyrazole.

To a solution of 100 mg. of N-acetyl-9a-fluoro-11B, 17a,2l-trihydroxy-l6a-methyl-20-oxo-4-pregneno-[3,2-c1- pyrazole in 2 m1. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. in vacuo. The 1 -acetyl-9ot-fiuoro- 1 113, 1706,21 trihydroxy-l 6a-methyl-20-oxo-4-pregneno-[3, 2-c]pyrazole 21-acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding N acetyl-9a-fiuoro-1 1B,17a,2l-trihydroxy-16a-methyl-20- oxo-4-pregneno- 3,2-c] pyrazole 21-acylate.

In accordance with the above procedure, but starting with the 9oz fiuoro-l118,17a,2l-trihydroxy-16u-methyl-20- oxo-4-pregneno-[3,2-c]pyrazole and using two milliequivalents of another acylating agent, there is obtained the corresponding N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-acyl-9a-fluoro-11B,l7a,21- trihydroxy-l6a-methyl-20-oxo-4-pregneno-[3,2-c1pyrazole ZI-acetate in 60 ml. of 80% (v./v.) acetic acid is refiuxed for 1.5 hours. This solution is diluted With 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness in vacuo. Recrystallization of the resulting product affords 9a fiuoro 11fl,17a,21-trihydroxy-16amethyl-20-oxo-4-pregneno-[3,2-c]pyrazole 21-acetate.

To a solution of 85 mg. of N-acetyl-9a-fluoro-115,17, 21 trihydroxy-16e-methyI-Z0-oxo-4-pregneno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-acetyl-9u-fluoro-11fl,17u,21- trihydroxy 16cc methyl 20 oxo-4-pregnene-20-one-21- mesylate.

To 180 mg. of N-acetyl-9a-fluoro-1'1;3,17a,21-trihydroxy-16u-methyl-20-oxo-4-pregneno[3,2-c]pyrazole 21- mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-acetyl-9a-fluoro-11,B,17a-dihydroxy-21-iodo- 16 t-methyl-20-oxo-4-pregneno- 3,2-c] PYrazole.

The N-acetyl-9ot-fluoro-11B,17a-dihydroxy-21-iodo-16amethyl-20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-acetyl-9a-fluoro 11,8,17ot dihydroxy 16umethyl-20-oxo-4-pregneno- [3,2-c]pyrazole.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9ot-flll0IO-11fi,-170tdihydroxy 16oz methyl-20-oxo-4-pregneno-[3,2-c]pyrazole.

To a solution of 62 mg. of N-acetyl-9u-fluorm115,17a, 21 trihydroxy-l6a-methyl-20-oxo-4-pregneno-[3,2-c1pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethyl-formamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chlorofiorm, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-acetyl- 1701,21 epoxy-9ot-fluoro-1lfl hydroxy-l6ot-methyl-20-oxo- 4-pregneno-[3,2-c1pyrazole and N-acetyl-9a,21-difluoro- 115,17a dihydroxy 16oz methyl-20-oxo-4epregneno-[3, 2-c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen at mosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and dried to constant weight to give 9a,21-difluoro- 17a,21 dihydroxy 16oz methyl 20-oxo-4-pregneno-l3, 2.-c]pyr-azole.

, In accordance wih the above procedures, but starting with the 9a-fluoro-11,8,17a,21-trihydroxy-16-methylene-4- pregnene-3,20-dione in place of the 9OL-flL1OI'O-11fi,170t,2'1r trihydroxy-16a-methyl-4-pregnene-3,20-dione, there are obtained as products the corresponding 9zx-fluO101-1 113,17a, 2 1 trihydroxy 16 methylene 1-1,20 dioxo 4 pregneno-[3,2-c1pyrazole and the N-acyl-, the 217acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two acyl groups may be the same or different; the 9a-fluoro 17a,21 dihydroxy 16 methylene 11,20 dioxo 4- pregneno-[3,2-c]pyrazole and the N-acyl derivatives thereof, and the 9a,21-difluoro-11,9,17a-dihydroxy-16-methylene-l1,20-dioxo-4-pregneno-[3,2-c]pyrazole and the N- acyl derivatives thereof. 7

A 500 mg. aliquot of the above product is dissolved in 2.4 ml. of pure methanol and allowed to react with- 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid 34 and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 9u,21-difluOr017a,2l-dihydroxy-16a-methyl-20-oxo-4-pregneno-[3,2-c]pyrazole.

Example 7 About 6 g. of 17ot,20,20,21-bis(methylenedioxy)-1118- hydroxy-16ot-methyl-4-pregnene-3-one (Example 4) is suspended in about 35 ml. of dry benzene, and to this suspension is added '6 ml. of ethyl formate and about 1 g. of freshly prepared sodium methoxide. The mixture is allowed to stand at room temperature under nitrogen for 1% hours and is then cooled in an ice bath. The mixture is then acidified with an excess of a saturated aqueous solution of potassium dihydrogen phosphate. Ether is added and the product is extracted several times with a 2% aqueous solution of sodium hydroxide. The extracts are back-extracted with ether which is acidified with cold 2.5 N HCl, and then extracted with methylene chloride. The methylene chloride extracts are washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate and then taken to dryness. The resulting product is crystallized with ether; petroleum ether to give 170:, 20,20,21 bis(methylenedioxy) 113 formyloxy 2- hydroxymethylene-16a-methyl-4-pregnene-3-one.

To 1.422 g. of 17a,20,20,21-bis(methylenedioxy)-115- formyloxy 2 hydroxymethylene 16oz methyl 4- pregnene-3-one, suspended in 18 m1. of absolute ethanol, is added 0.45 ml. of phenylhydrazine. The reaction mixture is refluxed for 40 minutes under nitrogen and then cooled. The 17u,20,20,21-bis(methylenedioxy)-1lB-formyloxy 16a methyl 2 phenyl 4 pregneno [3, 2-c]pyrazole, which is formed as the major product, separates out and is recrystallized.

The 17a,20,20,21-bis (methylenedioxy) -1 1 fi-formyloxy- 16a methyl 2 phenyl 4 pregneno [3,2-c]pyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed in vacuousing a water bath at about 50 C. as the source of heat. The residue is flushed four times with n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of 11,6,17a,2l-trihydroxy-16a-methyl-20-oxo-2-phenyl-4-pregneno-[3,2-c] -pyrazole and 11fl,17ot,21-trihydr0xy- 16a methyl 2O oxo 2 phenyl 4 pregneno [3, 2-c] pyrazole 2 l-formate.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 11,6,17a,21-trihydroxy- 16a-methyl-ZO-oxo-2-phenyl-4-pregneno-[3,2-c]pyrazole.

Example 8 To a solution of 0.5 millimole of 17a,20,20-2l-bis(methylenedioxy) 11p hydroxy 2 hydroxymethylene 16amethyl-4-pregnene-3-one (Example 4) in about 3 ml. of absolute ethanol is added 0.6 millimole of sodium acetate and ,then 0.6 millimole of methylhydrazine sulfate. The mixture is refluxed under nitrogen for 40 minutes and then filtered hot. The filtrate is taken to dryness, water is' added, and the 17a,20,20,21-bis(methylenedioxy)-N, 16a dimethyl 115 hydroxy 4 pregneno [3,2 c] pyrazole'which is formed as the major component is removed by filtration.

Alternately, a mixture of 1',16 x-dimethyl-, and 2',16adimethyl 1'7a,20,20,21 bis(methylenedioxy) 11 3 hydroxy-.4-pregneno-[3,2-c]pyrazole is prepared by heating 1'7u,20,20,21 bis(methylenedioxy) 11,8 hydroxy 2 hydroxymethylene 16a methyl 4 pregnene 3 one with methanol in the presence of p-toluenesulfonic acid to form the 17u,20,20,21-bis(methylenedioxy)-1 1,8-hydroxy 2 methoxymethylene 16oz methyl 4 pregnene-S-one, and then reacting the latter compound with methylhydrazine, following the detailed procedures given in columns 37 and 38, but using methylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

In accordance with all the above procedures, but using other alkyl substituted hydrazines such as ethyl-, fi-hydroxyethyl-, propyl-, butylhydrazines, and the like, in place of methylhydrazine, there are obtained the corresponding 1'-alkyland 2'-alkyl-l7a,20,20.21-bis(methylenedioxy) 11ft hydroxy 160a methyl 4 pregneno- [3,2-c]pyrazoles.

The 17a,20,20,21-bis(methylenedioxy)-N,16a-dimethyl- 11fl-hydroxy-4-pregneno-[3,2-c]pyrazoles may be prepared by the following procedure:

The 17a,2(),20,2 l-bis (methylenedioxy) -1 1 fi-hydroxy-Z- hydroxymethylene-l6ot-methyl 4 pregnene-3-one is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for one hour in high vacuum to give 17a,20,20,21-bis(methylenedioxy)-l lfi-hydroxy- 1 Git-methyl 4-pregneno-[3,2-c1pyrazole.

A solution of about 0.47 millimole of 17a,20,20,21-bi8 (methylenedioxy)-l lfi hydroxy 16oz methyl-4-pregneno- [3,2-c1pyrazole in .10 ml. of benzene is treated with about 30-38 mg. of about 51% sodium hydride (in oil suspen sion). After the addition of 2-3 ml. of dimethylformamide (dried over calcium hydride) and 5 ml. of methyl iodide, the mixture is stirred at room temperature over night. The product is filtered, washed with methylene chloride, and the filtrate and washings are taken to dryness. The residue is treated with Water and the product is filtered to attord as a major component the 17a,20,20, 21 bis(methylenedioxy) 11B hYdIOXY-NJGoc-dimethYL 4-pregneno-[3,2-c]pyrazole.

In accordance with the above procedure, but using another alkylating agent, for example, ethyl iodide, propyl iodide and the like, in place of the methyl iodide, there is obtained the corresponding N alkyl 17m,20,20,21-bis- (methylenedioxy) 115 hydroxy-l6ot-methyl-4-pregneno- [3,2-c]pyrazole.

The 17a,20,20,2l-bis(methylenedioxy) 11 3 hydroxy- 2,l6a-dimethyl-4-pregneno-[3,2-c]pyrazole (15 mg.) is heated on a steam bath with 1 ml. of 60% formic acid for about minutes and then filtered hot. The filtrate is taken to dryness, water is added, and a mixture of the 11,3,17u,21 trihydroxy 2,16tx dimethyl-20-oxo-4-pregneno-[3,2-c]pyrazole and its 2l-formate is recovered by filtration. A 500 mg. aliquot of this crudev product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 115, 1711,21 trihydroxy 2,l6u dimethyl-20-oxo-4-pregneno [3,2-c]pyrazole.

To a solution of 100 mg. of 11B,17a,21-trihydroxy-2', 16a-dimethyI-Z0-oxo-4-pregneno-[3,2-c1pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand overnight at room temperature. A mixture of ice and Water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is l3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layr is neutral). The ethyl acetate solution is dried with anhydrous sodium 36 sulfate. The solvent is then distilled at about 40 C. in vacuo. The 11,8,17ot,21-trihydroxy 2,16u dimethyl-20- oxo-4-pregneno-[3,2-c]pyrazole 21-acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding 115, l7a,2l-trihydroxy 2',16oz dimethyl-ZO-oxo-4-pregneno- [3,2-c]pyrazole 2l-acylate.

To a solution of mg. of 11 8,l7a,21-trihydroxy-2'- Mia-dimethyl 20 oxo-4-pregneno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give l1fi,17ot,2l trihydroxy-Z',l6ot-dimethyl-20- oxo-4-pregneno-[3,2-c]pyrazole 2l-mesylate.

To 180 mg. of 11B,17a,21-trihydroxy-2',16u-dimethyl- 20-oxo-4-pregneno-[3,2-c]pyrazole 2l-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give 11,8,17u-dihydroxy- 21-iodo-2,l6a-dimethyl 20 oxo-4-pregneno-[3,2-c1pyrazole.

The 1 1 [5, 17u-dihydroxy-2l-iodo-2',16u-dimethyl-20-oxo- 4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give 11 3,l7u-dihydroxy-2',16u-dimethyl-20 oxo-4-pregneno-[3,2-c]pyrazole.

To a solution of 62 mg. of 11B,17a,21-trihydroxy-2, 160a dimethyl 20 oxo-4-pregneno-[3,2-c]pyrazole 21- mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The re sulting product is a mixture of 17a,21-epoxy-11,3-hydroxy- 2',l6a dimethyl-ZO-oxo-4-pregneno-[3,2-c]pyrazole and pregneno-[3,2-c]-pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures beginning with the 2-methyl-17a,20,20,2l-bis(methylenedioxy)-11,8- hydroxy-4-pregneno-[3,2-c]pyrazo1e, but using the 1- methyl-derivative in place of the 2-methyl-derivative, there are obtained the corresponding 1-methyl compounds.

In accordance with all of the above procedures, but starting with the 17a,20,20,21-bis(methylenedioxy)-2-hydroxymethylene-4-pregnene-derivative which is obtained from each of the starting materials which are listed on pages 3-6, there are obtained the corresponding 1-methyland 2-rnethyl derivative.

Example 9 To 200 mg. of 17a,20,20,21-bis(methylenedioxy)-11phydroxy 2 hydroxymethylene-16u-methyl-4-pregnene-3- one (Example 4) in 7 cc. of absolute ethanol is added 82 mg. of sodium acetate and then 102 g. of cyclohexylhydrazine oxalate. The mixture is refluxed under nitrogen for one hour. The insolubles are removed by filtration. The filtrate is taken to dryness. The residue is dissolved in 3 cc. of ether and the ether solution is washed successively 37' with 2% aqueous sodium hydroxide and then with water to neutrality. The ether solution is then dried over magnesium sulfate, filtered and taken to dryness to give a residue which has as the major component the N-cyclohexyl 17a,20,20,21 bis-(methylenedioxy)-1Iii-hydroxyl6a-methyl-4-pregneno-[3,2-c]-pyrazole.

Alternately, a mixture of 1'-cyclohexyland the 2'- cyclohexyl 17cc,20,20,21 bis(methylenedioxy) 11B- hydroxy-4-pregneno-[3,2-c]pyrazole is prepared by heating 17a,20,20,2 l-bis (methylenedioxy) -1 lfi-hydroxy-Z-hydroxymethylene-16a-methyl-4-pregnene-3-one with methanol in the presence of p-toluenesulfonic acid to form the 17oc,20,20,21 bis (methylenedioxy)-1lfi-hydroxy-Z- methoxymethylene-16a-methyl-4-pregnene-3-one, and then reacting the latter compound with cyclohexylhyd-razine following the detailed procedures given on page 92, but using cyclohexylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

A 150 mg. aliquot of the N-cyclohexyl-17a,20,20,21- bis(methylenedioxy)-11fl-hydroxy-16a-methyl 4 pregneno-[3,2,-c]pyrazole is heated under nitrogen with 5 cc. of a 60% aqueous solution of formic acid for about 40 minutes. The mixture is taken to dryness and water is then added. The product is extracted with chloroform, and the chloroform solution is washed with saturated aqueous sodium chloride solution, 5% acqueous sodium bicarbonate solution and then with water. The chloroform solution is dried over magnesium sulfate, and then taken to dryness to give a residue. This is taken up in ether containing a little methanol, stirred with 75 mg. of Darco G60 (a decolorizing charcoal), filtered and taken to dryness to give N-cyclohexyl-l1/3,17u,21-trihydroxy-16a-methyl-20-oxo-4-pregneno- [3 2-c] -pyrazole.

The 2 cyclohexyl-l1B,17a,21-trihydroxy-16a-methyl- -oxo-4-pregneno-[3,2-c1pyrazole is converted into the 21 acetate, the 2 cyclohexyl 11/3,17u-dihydroxy-16amethyl-20-oxo-4-pregneno-'[3,2-c]pyrazole, and into the 2'-cyclohexyl-2 l-fluoro-l 16,17a-dihydroxy-16rx-methyl-20 oxo-4-pregneno-[3,2-c]pyrazole, following the detailed procedures given in Example 8 for the corresponding 2- methyl-derivatives.

In accordance with the above procedures beginning with the 2'-cyclohexyl-17a,20,20,21-bis(methylenedioxy)- 11B hydroxy 16oz methyl 4 pregneno [3,2-c1pyrazole, but using the 1'-cyclohexyl-derivative in place of the 2-cyclohexyl-derivative, there are obtained the corresponding 1'-cyclohexyl-compounds.

In accordance with all of the above procedures, but starting with the 17a,20,20,2l-bis(methylenedioxy)-2- hydroxymethylene-4pregnene-derivative which is obtained from each of the starting materials which are listed on pages 3-6, there are obtained the corresponding 1-cyclohexyl-and 2'-cyclohexyl-derivatives.

In accordance with the above procedures, but using other cycloalkylhydrazines in place of cyclohexylhydrazine there are obtained the corresponding l'- and 2-cycloalkyl derivatives. Example 10 A mixture of 90 mg. of 17a,20,20,21-bis(methylenedioxy) 1113 hydroxy 2 hydroxymethylene 16a methyl-4-pregnene-3-one and 0.028 ml. of phenylhydrazine are refluxed under nitrogen in 1.2 ml. of absolute ethanol for 50 minutes. The reaction mixture is taken todryness. Water is. added and the product is filtered to give an amorphous solid, which is Washed successively with water, dilute acid, water, and petroleum ether. The product is crystallized from methanol to give 17cc,20,20,21-bis- (methylenedioxy) llfi hydroxy- 16oz methyl 2'- phenyl-4-pregneno- [3 ,2-c] pyrazole.

H Alternately, a mixture of the 1-phenyl and 2'-phenyl 1'7a,20,20,21 bis(methylenedioxy) llfi-llYdlOXY-16ocmethyl-4-pregneno-[3,2-c]pyrazole is prepared by the following route: A mixturev of 1 gram of 17oc,20,20,21bi$ methylenedioxy) hydroxy 2 hydroxymethylene- 16u-methyl-4-pregnene-3-one, 200 ml. of methanol, and 200 mg. of p-toluenesulfonic acid is heated to reflux temperature and then allowed to stand at room temperature for one hour. The reaction mixture is then diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed two times with 2 N aqueous sodium hydroxide solution and then with water. The ehyl acetate extract is then dried and concentrated in vacuo. The 170c,20,20,2l bis(methylenedioxy) 11/3 hydroxy 2- metl'lyoxymcthylene-l6a-methyl-4-pregnene-3-one is obtained by direct crystallization or by chromatography on acid-washed alumina and elution with etherzchloroform mixtures.

A mixture of 500 mg. of (17a,20,20,21-bis(methylenedioxy) 11/3 hydroxy 2 methyoxymethylene 16amethyl-4-pregnene-3-one), 100 ml. of ethanol, and 1 ml. of phenylhydrazine is heated under nitrogen until dissolved, and then allowed to stand under nitrogen at room temperature overnight. Acetic acid (2 ml.) is added and the mixture is allowed to stand for another 4 hours. The

reaction mixture is then diluted with ethyl acetate, washed two times with 2 N sulfuric acid, two times with 2.5 N sodium hydroxide, and then two times with water. The ethyl acetate extract is then dried, concentrated, and chromatographed on acid-washed alumina. Elution with benzene affords a product which on recrystallization from a mixture of benzene and ethyl acetate affords the 17 0:,20, 20,21 bis(methylenedioxy) 11B hydroxy cmethyl l -phenyl-4-pregneno-[3,2-c]pyrazole. Further elution with a mixture of 1:1 ether: petroleum ether and crystallization from benzene, affords the 17a,20,20,2lbis (methylenedioxy) 11B hydroxy 16a methyl- 2'-phenyl-4-pregneno- 3,2-c] pyrazole.

A 30 mg. aliquot of 17a,20,20,21-bis(methylenedioxy)- 11B hydroxy 16oz methyl 2' phenyl 4 pregneno- [3,2-clpyrazole is heated on a steam bath with 2 ml. of 60% formic acid for 35 minutes. The solvents are removed in vacuo, water is added and the product is filtered oil? to give a mixture of 115,17u,21-trihydroxy-16a-methyl- 20-oxo-2'-phenyl-4-pregneno-[3,2-c]pyrazole and its 21- formate. The presence of formate is indicated by infrared absorption at 5.81 and 8.5g.

- A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for 10 minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with nhexane. The residue is washed with water, filtered and dried to constant Weight to give 11,3,17a,21-trihydroxy- 16a methyl 20 oxo 2' phenyl 4 pregneno- [3,2-c1pyrazole.

The 11/3,17a,21-trihydroxy-16oc-methyl-20-oxo-2'-phenyl-4-pregneno-[3,2-c]pyrazole is treated with a mixture of 1.5 ml. of pyridine and 1.5 ml. of acetic anhydride and the mixture is allowed to stand at room temperature overnight. The solvents are removed in vacuo, water is added and the 1l5,17a,2l-trihydroxy-l6a-methyl-20-oxo-2Z phenyl-4-pregneno-[3,2-c]pyrazole 21-acetate is removed by filtration. After drying, the compound is dissolved in methylene chloride, a few drops of 2.5 N HCl are added and the mixture is taken to dryness. The resulting 115,. 17u,21 trihydroxy 16a methyl 20 oxo -2' phenyl- 4-pregneno-[3,2-c]pyrazole ill-acetate hydrochloride salt is soluble in methylene chloride and can be crystallized from acetone.

The 11p,17a,21 trihydroxy 16a methyl 20 oxo- 2'-phenyl-4-pregneno-[3,2-c]pyrazole (100 mg.) is dissolved in 1.2 cc. of dimethylformamide. The solution is cooled to 0 C. and 0.07 cc. of methane sulfonyl chloride is added. The mixture is kept at 0 C. for about one hour, 3 cc. of water is added and the product is extracted into 100 cc. of chloroform, washed with water, dried over sodium sulfate and taken to dryness to afford the 11/3,

170:,21 trihydroxy 60:,160: dimethyl 20 oxo 2'- phenyl-4-pregneno-[3,2-c]pyrazole 2l-mesylate.

The 11,8,17a,21 trihydroxy 16a methyl 20 oxo- 2-phenyl-4-pregneno-[3,2-c]pyrazole 21-mesylate is suspended in 5.5 cc. of acetone and 117 mg. of sodium iodide is added. The mixture is refluxed under nitrogen for about one hour. It is then cooled on ice. On the addition of water there is formed a white precipitate which is filtered oflf, washed with water, and dried under vacuum to give the 1113,17m-dihydroxy-21-iodo-16a-methy1-20-oxo- 2'-phenyl-4-pregneno- 3,2-c1pyrazole.

The above material is dissolved in 5 cc. of ethanol. Five hundred mg. of sodium bisulfite in 5 cc. of water is added, and the mixture is refluxed for one hour under nitrogen. Ten cc. of water is then added and the product is extracted into 100 cc .of chloroform, washed with water, dried over sodium sulfate and taken to dryness, to give a residue which is purified by chromatography on silica gel. The 1113,17cc dihydroxy 16cc methyl 20- oxo-2'-phenyl-4-pregneno-[3,2-c]pyrazole so obtained is crystallized from acetone-ether.

Silver dihydrogen phosphate is prepared by the reaction of 32 g. of trisilver phosphate with m1. of 100% phosphoric acid with thorough mixing in a one-liter 3-necked round-bottomed flask. The silver dihydrogen phosphate is washed with two portions of diethyl ether, which are removed by decantation, to remove some of the phosphoric acid. About 200 ml. of acetonitrile are added to cover the silver dihydrogen phosphate, and the mixture is heated to reflux temperature. At this point g. of 113,171 dihydroxy-Zl-iodo 16a methyl-20-oxo-2'-phenyl-4-pregneno-[3,2-c]pyrazole is added and the mixture is refluxed in a nitrogen atmosphere with stirring for 75 minutes. The reaction mixture is then cooled over a period of about one hour to room temperature. Then 200 g. of ice water are added, and the acetonitrile is removed in vacuo at a temperature below 9 C. The pH of the resulting aqueous suspension is adjusted to 6.4 by the addition of 23 ml. of saturated aqueous sodium carbonate solution. A precipitate is formed and separated by filtration. The precipitate is Washed with water until no ultraviolet absorbing material is detected in the wash water. The filtrate and wash water are combined and freeze dried to separate a solid material from the water. The solid material is triturated with a total of 770 ml. of methanol in seven portions. The methanol-insoluble material is separated by filtration. The filtrate is then concentrated in vacuo to 200 ml. and passed through a column containing 60 g. of a cation exchange resin (IR-120) in its hydrogen form. The column is washed with methanol until the washings contain no ultraviolet absorbing material. The combined eluate and washings are concentrated to a volume of 15 ml., and 150 ml. of ether are added. The precipitate which forms is recovered by filtration, washed with ether, and dried for about 16 hours in a desiccator, to give 11,8,17a-dihydroxy-l6a-methyl-Z0-oxo-2'-phenyl-4- pregneno-[3,2-c]pyrazole 21- dihydrogen phosphate.

The monoand the dialkali metal salts of the 21-dihydrogen phosphate compound are obtained by neutralizing the ZI-dihydrogen phosphate ester with an alkali metal methoxide.

To a solution of 62 mg. of 1113,170:,21-t1ihYd1'0XY-16amethyl-20-oxo-Z'-phenyl-4-pregneno-[3,2 c]pyrazole 21- mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of 17a,2l-epoxy-1lfi-hydroxy- 16a-methyl-20-oxo-2'-phenyl-4-pregneno-[3,2 c] pyrazole and 2l-fluoro-l1,8,17a-dihydroxy 16oz methyl-20-oxo-2'- phenyl-4-pregneno-[3,2-c]pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures beginning with the 2' phenyl 17a,20,20,2l bis(rnethylenedioxy)-11B- hydroxy-l6a-methyl-4-pregneno [3,2-c]pyrazole, but using the 1'-phenyl-derivatives in place of the 2'-pheny1-derivatives, there are obtained the corresponding 1-phenylcompounds.

In accordance with all of the above procedures, but starting with the 17a,20,20,2l-bis(methylenedioxy)-Z-hydroxymethylene-4-pregnene derivative which is obtained from each of the starting materials which are listed on pages 3-6, there are obtained the corresponding 1'-phenyland 2'-phenylderivatives.

Example 11 To a mixture of 223 mg. of 17a,20,20,2l-bis(methylenedioxy) -l lfi-hydroxy 2 hydroxymethylene-l 6a-methyl-4- pregnene-3-one (Example 4) in 5 ml. of absolute ethanol is added 49 mg. of sodium acetate and then mg. of p-tolylhydrazine hydrochloride. The mixture is refluxed under nitrogen for 45 minutes. On cooling, a solid precipitates which is filtered. The filtrate is taken to drye ness and water is added. The product is filtered, washed with water, dilute acid, and again with water until neutral to aiford a solid which has as the major component the l7m,20,20,2l-bis(methylenedioxy) 11,3 hydroxy 16amethyl-2-(p-tolyl) 4 pregneno-[3,2-c1pyrazole. The product is purified by dissolving 235 mg. of the crude material in 30 cc. of methanol and stirring at room temperature with 235 mg. of Nuchar C1000N (a decolorizing charcoal). The mixture is filtered and the filtrate is concentrated and then crystallized to give 17cc,2(),20,21 bis(methylenedioxy)-1l/s-hydroxy 16a methyl 2 (ptolyl)-4 pregneno-[3,2-c]pyrazole.

Alternately, a mixture of 1-(p-tolyl)- and 2'-(p-tolyl)- 17 a,20,20,21-bl$ (methylenedioxy) llfi hydroxy-4-pregneno-[3,2-c]pyrazole is prepared by heating 17a,20,20,21-. bis(methylenedioxy)-1lfl-hydroxy 2 hydroxymethylenel6a-methyl-4-pregnene-3-one with methanol in the presence of p-toluenesulfonic acid to form the 17a,20,20,21- bis(methylenedioxy)-11fi-hydroxy 2 methoxymethylene-l6a-methy1-4-pregnene-3-one, and then reacting the latter compound with p-tolylhydrazine following the detailed procedures given in columns 37 and 38, but using p-tolylhydrazine instead of phenylhydrazine in the second step of the reaction. The components of the mixture are separated by chromatography.

A 13 mg. aliquot of the 2-(p-tolyl)-17a,20,20,21-bis (methylenedioxy-l lfl-hydroxy 16a methyl-4-pregneno-v [3,2-c]pyrazole is heated on a steam bath with 1 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The mixture is taken to dryness, water is added and the product is filtered off to give 11B,17a,2l-trihydroxy- 16la-methyl-20-oxo-2'- (p-tolyl) 4 pregneno-[3,2-c]pyra- 20 e.

The 11B,17a,21-trihydroxy 16o: methyl-20-oxo-2'-(ptolyl)-4-pregneno-[3,2-c]pyrazole is treated with a mixture of 1.5 ml. of pyridine and 1.5 ml. of acetic anhydride and the mixture is allowed to stand at room temperature overnight. The solvents are removed in vacuo, water is added and the 11,8,17a,21-trihydroxy-16a-methyl-20-oxo- 2-(ptolyl)-4-pregneno-[3,2-c]pyrazole 21-acetate is removed by filtration. After drying, the compound is dissolved in methylene chloride, a few drops of 2.5 N HCl are added and the mixture is taken to dryness. The resulting 11/8,17a,2l-trihydroxy-16a-methyl-20-ox0-4-pregneno-[3,2-c]pyrazole 21-acetate hydrochloride is soluble in methylene chloride and can be crystallized from acetone.

In accordance with the above procedure, but adding an equivalent amount of sulfuric acid, chloric acid, perchloric acid, picric acid or trichloroacetic acid in place of the hydrochloric acid the corresponding sulfate, chlorate, perchlorate, picrate or trichloroacetate salt is formed.

The 11B,17a,21-trihydroxy 16a methyl-20-oxo-2'-ptolyl-4-pregneno-[3,2-c]pyrazole is converted into its 21- 

2. A COMPOUND SELECTED FROM THE GROUP OF COMPOUNDS HAVING STRUCTURAL FORMULAS A AND B:
 3. A COMPOUND SELECTED FROM THE GRROUP CONSISTING OF 17A,21-DIHYDROXY-16A-METHYL-11,20-DIOXO-4-PREGNENO(3,2-C)PYRAZOLE AND THE N-LOWER HYDROCARBON CARBOXYLIC ACYL-, 21--LOWER HYDROCARBON CARBOXYLIC ACYLATE AND NLOWER HYDROCARBON CARBOXYLIC ACYL-21-LOWER HYDROCARBON CARBOXYLIC ACYLATE DERIVATIVES THEREOF. 